This competitive renewal of our Program Project Grant, Center of Excellence for Research on Complementary and Alternative Medicine (CAM) Antioxidant Therapies (CERCAT), which was one of the first two CERCs funded by NCCAM in 2003, combines the scientific and research expertise of many faculty from the Linus Pauling Institute at Oregon State University and the clinical and medical expertise from faculty at Oregon Health & Science University. The Linus Pauling Institute has established itself as a national and international leader in research and education on micronutrients and antioxidants, and is one of a few research centers in the U.S. to focus entirely on increasing human healthspan - the period of a person's life during which they are generally healthy and free from serious or chronic illness - by dietary, lifestyle, and complementary medicine means. The results from the current funding period of the grant have lead to a paradigm shift in our understanding of how natural antioxidants function in the body, viz., not only by scavenging free radicals and preventing oxidative damage to biological macromolecules, but also through more subtle, yet profound changes in reduction-oxidation (redox)-sensitive processes inside cells. This new knowledge is fostering the development of new CAM modalities that reverse cell and tissue dysfunctions by re-setting intracellular signal transduction, transcription factor activation, and gene expression to normal, healthy levels. Hence, the goals of this competitive renewal of CERCAT are to better understand the molecular and cellular mechanisms of action and to test the in vivo efficacy - both in experimental animals and humans - of redox-active CAM modalities that have the potential to substantially improve the body's resistance to chronic disease and aging. These goals will be accomplished through three highly interactive projects: 1) Lipoic acid supplementation to reduce risk factors for atherosclerosis in humans (Dr. Balz Frei, Project Leader); 2) Lower vulnerability to toxins in aging by treatment with lipoic acid (Dr. Tory Hagen); and 3) CAM antioxidants in amyotrophic lateral sclerosis (Dr. Joseph Beckman). Center Investigators will be aided by an Administrative Core, which handles budgetary, reporting, and external advisory needs. In summary, CERCAT will provide an integrated set of mechanistic studies for the redox-active compound, (R)- a-lipoic acid, and other CAM antioxidants at the cellular and molecular level, and develop the proof of concept of their therapeutic value in suitable animal models and humans. We expect to make significant advances in the identification of the molecular and cellular mechanisms and relevant biological targets of these CAM antioxidants and - by discovering both beneficial and potentially harmful effects in vivo - to establish their safety and efficacy. This knowledge will help identify and develop new CAM modalities that enhance individual and public health and increase healthspan through affordable, safe, and effective means.